1. Field of the Invention
The present invention generally relates to a novel medium molecular weight heparin, its preparation and use.
2. Description of the Related Art
Heparin was discovered by MacLean in 1916 and has been employed in medicine for more than 60 years. Its main field of application is antithrombotic prophylaxis and therapy. Meanwhile, heparin is used in medicine in two different forms. The first form is unfractionated heparin (UFH) which is recovered on an industrial scale from the lungs, livers or intestinal mucosae of cattle and pigs, and is obtained after proteolysis, separation of undesirable accompanying materials, such as fat and proteins, and bleaching. The second form is low molecular weight heparins (LMWH) which are obtained by the depolymerization of UFH.
The essential difference in the application of these two heparins resides in their different bioavailabilities. After subcutaneous injection of UFH, this is about 10–20% of the administered dose, while the bioavailability of LMWH is around 90% (R. J. Kandotas, Heparin Pharmacokinetics and Pharmacodynamics, Clinical Pharmacokinetics, 22(5): 359–374, 1992).
In the following Table 1, the essential characteristics of UFH and LMWH are listed for comparison (J. Hirsh and M. N. Levine, “Low molecular weight heparine”, Blood 79(1): 1–17, 1992).
TABLE 1UFHLMWHMolecular weight (in Dalton)3000–30,0002000–8000Average molecular weight (in Dalton)13,0005000Anti-Xa/anti-IIa activity1:12:1–5:1Neutralization by PF 4*strongweakBinding to proteinshighlowBinding to endothelial cellsyesweakDose-dependent clearanceyesnoBioavailability (s.c.)10–25%about 90%Half-lives (t½)1 h (i.v.)2 h (i.v.)1–2 h (s.c.)3–6 h (s.c.)EliminationbiophasicrenalLaboratory controlsrequirednot required*PF 4 = a plasma protein called platelet factor 4
In clinical applications, UFH and LMWH are essentially employed for the prophylaxis and therapy of thrombo-embolic diseases, LMWH only recently having found increased use. All in all, the peri- and post-operative thrombotic risk could be reduced by the use of these heparins from 50 to 60% to about 15 to 30% (J. Harenberg, S. Haas, and K. H. Breddin, “Prophylaxe der venösen Thrombose” in Müller-Berghaus, G. Pötsch (Ed.), “Hämostaseologie”, Springer Verlag, Berlin-Heidelberg, pages 564 to 580, 1998). The achieved reduction of the peri- and post-operative thrombotic risk to 15 to 30% shows that there is a need for a further reduction of the thrombotic risk, and that is why research seeks to develop improved alternatives.
The development of hirudine, a direct thrombin inhibitor, provided some improvement because a more extensive protection became achievable. However, the use of hirudine is restricted to special problem cases, e.g., heparin intolerance, treatment of heparin-induced thrombocytopenia (HIT), because an antidote to heparin does not exist and thus there is a risk of uncontrollable bleedings.
Despite all the differences between the individual preparations, LMW heparins are rated clinically equivalent and routinely combined in meta analyses. However, they are superior to UFH in orthopedics or in surgical hip joint replacement only with respect to effectiveness, but there are no differences in tolerability. In the predominant application field of general surgery, LWMH and standard heparin prove to be constantly equivalent. This is true at least for the main criteria of antithrombotic protection and tendency to bleeding.
The equivalence of the individual LMW heparins in clinics is in contrast to the differences in average molecular weight, molecular weight spectrum, the percent anti-FXa and anti-FIIa activities and the influence on APTT, a coagulation time which indicates the inhibition of endogenous thrombin activity (by heparin). The list of differences further comprises pro-fibrinolytic activity, release of TFPI (tissue factor pathway inhibitor), influence on platelet function, etc.
To parallel the laboratory-medical variety of the individual products, there is no possibility of a superior clinical control of effectiveness which could determine the development of a new heparin.
To conclude, therefore, there are no indications of how to optimize heparins with respect to therapeutic width as a ratio of effectiveness and tolerability.
Therefore, it has been the object of the present invention to provide an active substance having anti-coagulant activity and thus to enrich the prior art by at least one further active substance, which active substance is to overcome at least part of the drawbacks known from the prior art.
Further, it has been an object of the present invention to provide a use for the active substance according to the invention.